Genetic circuitry governing heart growth and repair

控制心脏生长和修复的遗传电路

• 批准号: 10770716
• 负责人: Guo Huang
• 金额: $ 9.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770716
• 关键词: Acute; Adrenergic Receptor; Adult; Animals; Applications Grants; B-Cell Activation; B-Cell Lymphoma 6 Protein; BCL6 gene; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Chemicals; Clinical Treatment; Data; Development; Evolution; Genes; Genetic; Genetic Models; Growth; Heart; Heart Diseases; Heart failure; Heterocephalus; Human; Image; Injury; Knowledge; Light; Loss of Heterozygosity; Mammals; Methods; Microscopy; Mole Rats; Mus; Mutant Strains Mice; Myocardial Infarction; Nerve; Newborn Infant; Pathway interactions; Patients; Phenotype; Phylogeny; Physiological; Process; Proliferating; Publishing; Receptor Activation; Regenerative capacity; Regulation; Reporting; Repression; Rodent; Role; Science; Signal Transduction; Stains; Thermogenesis; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Transcription Repressor; United States; Up-Regulation; Viral Vector; Weight; Withdrawal; Work; Zebrafish; cardiac regeneration; cardiac repair; coronary fibrosis; differential expression; experimental study; heart dimension/size; heart function; hormonal signals; improved; inhibitor; injury and repair; insight; ischemic injury; mortality; mouse genetics; mutant; myocardial injury; novel; organ regeneration; postnatal; regeneration potential; regenerative repair; repaired; response to injury; self-renewal; synergism; transcription factor; transcriptome sequencing; treatment strategy

Project Summary/Abstract Current available clinical treatments greatly reduced the acute mortality of myocardial infarction. However, lost cardiomyocytes during myocardial injury still cannot be replenished, leading to a steady increase of heart failure patients. In contrast, adult zebrafish and newborn mammals are capable of robust cardiac regeneration. This process has been shown to rely on proliferation of preexisting cardiomyocytes after injury. In rodents, such an ability is lost within the first week after birth when the majority of cardiomyocytes undergo permanent cell-cycle arrest. However, the physiological triggers of this transition remain largely unknown. Our recently published work suggests that activation of thermogenic pathways during the acquisition of endothermy in ontogeny and phylogeny may cause a loss of cardiomyocyte proliferative and regenerative capacity (Hirose et al., 2019 Science). Following this direction, we discover that increases of neurohormonal activities associated with postnatal thermogenesis drive cardiomyocyte cell-cycle exit, at least in part by turning on B cell lymphoma 6 (Bcl6), a transcription factor previously unappreciated in the heart field. Moreover, Bcl6 is also identified in our RNA-seq analysis of all 1179 annotated mouse transcription factors as one of the top candidates that may induce postnatal loss of cardiac regenerative potential. Intriguingly, cardiac expression of Bcl6 increases 19 folds after birth in mice but not in naked mole-rats (Heterocephalus glaber), a poikilothermic rodent. The function of Bcl6 in cardiomyocytes have never been reported. Our preliminary data show that cardiomyocyte- specific deletion of Bcl6 in mice leads to enhanced cardiomyogenesis both in heart growth and after ischemic injury. We further identify a putative direct target gene of Bcl6, and demonstrate its major contribution to the phenotypes through genetic rescue experiments in mice. Based on these results, this grant proposal will apply a novel method that integrates whole-heart clearing, immunostaining and volume imaging by light-sheet microscopy to accurately assess the total cardiomyocyte number, and exploit mouse genetic models to elucidate the functions of Bcl6 and its downstream target in cardiomyocyte cell-cycle control during postnatal heart growth and adult myocardial injury repair. The regulation of Bcl6 in ontogeny and its expression in phylogeny will be further investigated to understand whether and how its expression increases in parallel with the development and evolution of endothermy. Altogether, this work will yield significant knowledge about the physiological brake of cardiac regeneration, and may offer novel treatment strategies to enhance heart regenerative repair in adult mammals.

项目概要/摘要 目前可用的临床治疗大大降低了心肌梗塞的急性死亡率。然而，失去了 心肌损伤时心肌细胞仍无法得到补充，导致心率持续升高 失败患者。相比之下，成年斑马鱼和新生哺乳动物具有强大的心脏再生能力。 该过程已被证明依赖于损伤后先前存在的心肌细胞的增殖。在啮齿类动物中， 这种能力在出生后第一周内就会丧失，此时大多数心肌细胞会经历永久性的转变。 细胞周期停滞。然而，这种转变的生理触发因素仍然很大程度上未知。我们最近 已发表的研究表明，在获得吸热过程中产热途径的激活 个体发育和系统发育可能导致心肌细胞增殖和再生能力丧失（Hirose 等 等人，2019 年《科学》）。沿着这个方向，我们发现神经激素活动的增加与 产后产热驱动心肌细胞细胞周期退出，至少部分是通过开启 B 细胞淋巴瘤 6 (Bcl6)，一种以前在心脏领域未被重视的转录因子。此外，Bcl6 还被鉴定为 我们对所有 1179 个带注释的小鼠转录因子进行 RNA-seq 分析，将其视为可能的最佳候选因子之一 导致出生后心脏再生潜力的丧失。有趣的是，Bcl6 的心脏表达增加 19 小鼠出生后会折叠，但裸鼹鼠（Heterocephalus glaber）（一种变温啮齿动物）则不会。这 Bcl6在心肌细胞中的功能尚未见报道。我们的初步数据表明，心肌细胞 小鼠体内 Bcl6 的特异性缺失可增强心脏生长过程中和缺血后的心肌生成 受伤。我们进一步确定了 Bcl6 的假定直接靶基因，并证明了其对 通过小鼠基因拯救实验研究表型。根据这些结果，该拨款提案将适用 一种集全心透明化、免疫染色和光片体积成像于一体的新方法 显微镜准确评估心肌细胞总数，并利用小鼠遗传模型 阐明 Bcl6 及其下游靶标在产后心肌细胞周期控制中的功能 心脏生长和成人心肌损伤修复。 Bcl6在个体发育中的调控及其在体内的表达 将进一步研究系统发育，以了解其表达是否以及如何与 吸热的发展和演变。总而言之，这项工作将产生关于以下方面的重要知识： 心脏再生的生理制动，并可能提供增强心脏功能的新治疗策略 成年哺乳动物的再生修复。